Despite prophylactic immune suppression, clinically significant (Grade II-IV) acute graft-versus-host disease (aGvHD) afflicts up to 45% of pediatric patients receiving allogeneic hematopoietic cell transplantation (alloHCT). As aGvHD is responsible for nearly 20% of deaths following alloHCT, the need for better prevention and therapy for aGvHD is readily apparent. Involvement of the gastrointestinal (GI) tract in the pathogenesis of aGvHD has been substantiated by the translation of pre-clinical and clinical studies. Emerging evidence suggests that perturbations in the microbiota diversity result in aberrant systemic immune response as well as pathogen colonization and mucosal invasion, fostering the development of GvHD. Pre-clinical studies also suggest that replenishing commensals like Lactobacillus prior to HCT substantially decrease GvHD severity and intestinal insult. Our pilot data suggest that probiotics are safe to administer prior to and during children and adolescents undergoing HCT (IND#108,977). This proposal is a double-blind, randomized, multi-center intervention trial to evaluate the specific effect of probiotics in preventing GI aGvH and more generally the effects on overall GvHD severity. The proposal is an approved concept of Children's Oncology Group's (COG), a NCI National Clinical Trial Network group. The study will be conducted through COG using its clinical research infrastructure. Correlative laboratory studies (plasma and stool analysis) will be performed in order to elucidate the mechanisms of action of probiotic therapy. The probiotic, Lactobacillus plantarum (LBP), or placebo will be administered to 384 evaluable children and adolescents undergoing alloHCT for hematologic malignancy beginning with the initiation of conditioning through Day 56. We hypothesize that maintaining epithelial cell integrity through the administration of probiotic therapy will lead to restoring microbial diversity, which will preserve immune tolerance and prevent aGvHD. The primary study aim is to determine whether oral LBP prevents the development of GI aGvHD and more severe (Grade II-IV) aGvHD in children and adolescents undergoing alloHCT. Secondary aims are: (1) Secondary Aim 1: Determine whether LBP administration maintains intestinal integrity as measured by plasma citrulline levels, and reduces the incidence of mucosal barrier bloodstream infections in alternative donor HCT patients. (2) Secondary Aim 2a: Examine the effects of LBP introduction on the intestinal flora phylogenetic composition of pediatric HCT recipients during and after HCT, assayed by 16S rRNA gene deep sequencing; and, (3) Secondary aim 2b: Evaluate the effects of LBP introduction on intestinal flora function during and after HCT, assayed by metagenomic and metabolite profiling. The proposed study will be the first double-blind randomized controlled trial to evaluate the effect of probiotics in preventig GI aGvHD in pediatric HCT. If a beneficial effect is observed, expansion of the proposed intervention to other pediatric and adult malignant conditions requiring alloHCT may improve overall quality of life and prevent transplant-related complications like aGvHD.